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Ayruvedic medical practitioners in Sri Lanka use aqueous extracts of the mature leaves of Osbeckia aspera to treat liver disease. The extract has been shown to have hepatoprotective effects in vitro and in vivo, and to have inhibitory effects on the complement system and on in vitro phagocytosis by polymorphonuclear cells. The aim of this study was to investigate the effect of an aqueous extract of Osbeckia on lymphocyte proliferation stimulated by mitogens and antigen. In control peripheral blood mononuclear cells (PBMC), high concentrations of the Osbeckia extract were inhibitory to proliferation stimulated by phytohaemagglutinin (PHA) and tuberculin purified protein derivative (PPD). On stimulation by phorbol myristate acetate and ionomycin (PMA+I) the extract showed stimulation of proliferation at low concentrations (<10 microg/ml) with inhibition at higher concentrations. A similar inhibitory pattern on mitogen/antigen stimulation was seen with PBMC from patients with chronic hepatitis C virus (HCV) infection. These results suggest that the inhibitory agent(s) in the aqueous extract of Osbeckia may have an effect on antigen-presenting cell function. The combined hepatoprotective and immunosuppressive effects of the extract are more likely to be beneficial in acute hepatitis rather than chronic hepatitis viral infection.

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BACKGROUND/AIMS: We investigated the antiviral and immunomodulatory effects of a combination treatment using thymus humoral factor-gamma 2 and alpha-interferon in patients with chronic hepatitis B in whom previous monotherapy with interferon had failed. METHODS: Nine HBeAg and HBV-DNA seropositive patients received thymus humoral factor-gamma 2 alone for 2 months, thymus humoral factor-gamma 2 plus alpha-interferon for 2 months and finally alpha-interferon alone for 2 months. RESULTS: Treatment with thymus humoral factor-gamma 2 alone was not associated with any side effects. The interferon-induced lymphopenia was significantly less marked during the combined therapy in comparison to the previous course with interferon alone (mean reduction of lymphocyte counts 33.5 +/- 11.6% versus 56.3 +/- 16.7%, respectively, p < 0.05). The combination of thymus humoral factor-gamma 2 plus interferon showed a significantly more profound inhibition of serum HBV-DNA (mean reduction from the pretreatment level 90.6 +/- 13.3%) compared to the earlier monotherapy with interferon in the same patients (mean reduction 55.5 +/- 34.7%, p < 0.01). As a result of the combined thymus humoral factor-gamma 2 plus alpha-interferon regimen three out of nine patients became HBV-DNA negative and seroconverted to anti-HBe. Thymus humoral factor-gamma 2 appears to exert mainly a functional effect on T lymphocytes, as interleukin-2 production was increased in the majority of treated patients, whilst the expression of lymphocyte activation markers remained unchanged. CONCLUSIONS: These data suggest that thymus humoral factor-gamma 2 may be useful in a combined therapeutic approach in chronic HBV carriers.

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A recent study indicated that thymic hormones have antiviral effects in human hepatitis B virus infection and woodchuck hepatitis virus infection. These hormones are known to exert immunomodulatory effects on lymphocyte maturation and function; because these are abnormal in patients with chronic hepatitis B virus infection, we have examined the effects of a thymic hormone (THF gamma 2) on peripheral blood mononuclear cells from patients with chronic hepatitis B virus infection. THF gamma 2 (50 or 150 ng/ml) alone was without effect; in the presence of low doses of the mitogen phytohaemagglutinin, it had a broad effect in patients and controls. The effect on interleukin-2 production was greater in patients than controls with a significant increase in production at 150 ng/ml for patients alone (p = 0.037). Tumour necrosis factor alpha production was enhanced in all patients and controls, with a greater effect seen at 150 ng/ml THF gamma 2 than 50 ng/ml. There was no effect on interferon gamma production or on the expression of membrane markers of T-cell activation. THF gamma 2 has substantial immunomodulatory activity in chronic hepatitis B virus carriers and in vivo assessment of THF gamma 2 in chronic hepatitis B virus is indicated.

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The cellular localisation of hepatitis B virus (HBV)-DNA in liver tissue was studied by in situ hybridisation using biotinylated and radiolabelled probes on samples from HBsAg carriers with a spectrum of disease and related to the presence of HBV-DNA in serum and intrahepatic HBcAg expression. Sixteen of the 31 patients studied were seropositive for HBV-DNA; nine had chronic active hepatitis and seven had chronic persistent hepatitis. HBV-DNA was detected in the liver tissue in seven of these patients. In each, HBV-DNA was detected in both cytoplasm and nuclei. All seven also had nuclear and/or cytoplasmic HBcAg which in six was associated with chronic active hepatitis. HBcAg (without tissue HBV-DNA) was detected in the remaining nine patients with an exclusively nuclear pattern in two. Fifteen patients were seronegative for HBV-DNA. HBV-DNA was not detected in the tissue of any of these. Three of these were HBcAg positive but in each this was confined to occasional nuclei and each had inactive disease. The close association between the presence of detectable HBV-DNA in tissue, cytoplasmic HBV-DNA expression and chronic active hepatitis in one group and a failure to detect HBV-DNA in those with nuclear HBcAg and benign disease suggests that there may be two distinct patterns of HBV replication in chronic HBV carriers which may influence the development of liver damage.

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To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the efficacy of subsequent IFN-alpha therapy in the treatment of chronic hepatitis B, a randomized trial was conducted to compare IFN-alpha priming (IFN-alpha for one month; no treatment for one month) followed by IFN-alpha therapy for three months, with IFN-alpha therapy (10 MU thrice-weekly) given for three months. Thirty-seven patients seropositive for more than six months for HBsAg, HBeAg and HBV DNA, and with histological evidence of active liver inflammation, were recruited. Eight patients (40%) treated with a priming course of IFN-alpha responded to subsequent IFN-alpha therapy for three months with loss of HBV DNA and HBe seroconversion. This compared with five patients (29%), treated only with IFN-alpha therapy for three months, who lost HBV DNA and HBeAg (but only two [12%] developed anti-HBe). IFN-alpha was well tolerated, with only three patients withdrawing from the study because of 'flu'-like symptoms or inconvenience in the early phase. The better response, although not significant, may suggest a place for a short priming course of IFN-alpha in addition to the current IFN-alpha treatment regimen.

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Because of widely differing reports on the significance of IgM anti-HBc in chronic hepatitis B virus (HBV) infection, paired sera and liver biopsies from 49 patients with chronic HBV infection were analysed for serum IgM anti-HBc, HBsAg titre, HBeAg/anti-HBe, HBV DNA, serum aspartate transaminase, intrahepatic HBcAg expression, and liver histology. High levels of IgM anti-HBc, in the diagnostic range of acute hepatitis B (greater than 1.2), were detected in seven patients (14.3%) and a total of 34 patients (69.6%) had an index of more than 0.2. No correlation was found between IgM anti-HBc and the serum markers of active viral replication or HBsAg titre but it correlated significantly with intrahepatic expression of cytoplasmic HBcAg (r2 = 0.165, P = 0.002). IgM anti-HBc also correlated with active liver histology (P = 0.015) but there was a considerable overlap of the IgM anti-HBc index values between the various disease groups, indicating a poor specificity. Serial assessment of IgM anti-HBc in eight patients treated with interferon-alpha (four responders) showed an increase in IgM anti-HBc in three out of four patients corresponding to the e-seroconversion period followed by a drop in IgM anti-HBc levels. However, an increase in IgM anti-HBc was also seen in one non-responder, indicating that this feature is not unique to interferon-alpha responders. These data indicate that serum IgM anti-HBc cannot be used alone as a certain diagnostic measure of HBV replication nor in the prediction of liver histology.

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The implications of hepatitis B virus (HBV) reinfection after liver transplantation were studied in 29 patients followed for 1.7-15 years. Of 20 patients with HBV infection alone, nine were HBeAg and HBV DNA seronegative and 11 had evidence of HBV replication as measured by HBeAg or HBV DNA seropositivity. Nine patients had co-existing HBV and delta virus (HDV) infection. Five patients became HBsAg seronegative after transplantation (four immediately and one after an hepatitic episode). Of the 20 patients with HBV infection alone, 17 had evidence of viral replication after transplantation with markedly increased HBV DNA levels. Five patients with HDV infection had HBV DNA in serum, but in significantly lower amounts than in those with HBV infection alone. Twenty-five episodes of graft dysfunction attributed to recurrent HBV infection occurred in 19 patients (65.5%). Thirteen episodes (in 12 patients) were self-resolving acute hepatitic illnesses. Six patients had a rapidly progressive illness leading to graft loss within 6 weeks, with the distinctive histological features termed fibrosing cholestatic hepatitis (FCH). Liver function tests in these patients showed markedly abnormal serum bilirubin and prothrombin times, but only modest increases in serum transaminase levels. An additional six patients lost their graft as a consequence of HBV recurrence through various pathogenetic mechanisms including possible (but unproven) FCH, chronic active hepatitis or late-onset hepatic failure. Co-existing HDV infection appeared to confer some medium-term protection from graft loss.

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The sensitivity of four different non-radiolabelled HBV-DNA probes (digoxigenin-, biotin-, acetylaminoflorene-, chemiprobe-labelled) in detecting HBV-DNA were compared with a 32P-labelled HBV-DNA probe using a spot hybridisation assay. Of the non-radiolabelled probes, the probe using digoxigenin labelling was the most sensitive with reliable and reproducible detection to between 1-3 pg HBV-DNA. The use of digoxigenin-labelled HBV-DNA hybridisation assay deserves wider application for the detection of HBV-DNA because of a number of advantages including ease, speed, safety and cost.

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Tumour necrosis factor-alpha (TNF-alpha), a cytokine derived from macrophages, is considered to be an important endogenous mediator of endotoxic shock. Patients with fulminant hepatic failure are particularly susceptible to infection and the development of multi-organ failure and similarities to endotoxic shock suggest a possible pathogenetic role for TNF in fulminant hepatic failure. In vitro TNF production was therefore investigated serially in 21 consecutive patients with fulminant hepatic failure and in 21 healthy controls. Spontaneous and lipopolysaccharide-stimulated TNF production were elevated in viral-induced fulminant hepatic failure, compared with healthy controls (P less than 0.05 and P less than 0.01, respectively). By contrast, patients with paracetamol-induced fulminant hepatic failure had normal spontaneous and lipopolysaccharide-stimulated TNF production, while those who died had significantly reduced spontaneous TNF production compared with survivors (P less than 0.02); this difference was present throughout admission. In this group elevations in TNF production above baseline were associated with Gram-positive bacterial or fungal infection but not Gram-negative bacterial infection. There was no correlation between any of the clinical complications of fulminant microbial stimuli in fulminant hepatic failure, but do not support a direct role for TNF in the evolution of the clinical complications of fulminant hepatic failure.

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Seven chronic carriers of hepatitis B virus (HBV) were studied during treatment with interferon-alpha to determine whether tumour necrosis factor alpha (TNF alpha) or interleukin-1 beta (IL-1 beta) contributed to the elimination of HBV. Four patients responded to interferon-alpha with clearance of HBeAg and permanent inhibition of HBV replication within 3-12 weeks; in each of these patients, the changes were accompanied by substantial rises in spontaneous in-vitro production of TNF alpha and IL-1 beta by peripheral blood mononuclear cells from previously undetectable levels. There was little or no change in spontaneous TNF alpha and IL-1 beta production in the three patients who did not lose HBeAg in response to interferon-alpha. These findings suggest that TNF alpha and IL-1 beta may contribute to the permanent elimination during interferon-alpha treatment of hepatocytes supporting viral infection and that the therapeutic potential of these cytokines is worthy of investigation.

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Foscarnet (trisodium phosphonoformate) is a novel antiviral agent that inhibits viral-specific DNA polymerase. In the present study, eight males with chronic HBV carriage (HBeAg and HBV-DNA seropositivity greater than 12 months) showing chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH) on liver biopsy received either a continuous infusion of foscarnet at 0.15 mg/kg/min for 7 days or 180 mg/kg/day divided into three daily boluses for 2 weeks. In all eight, HBV-DNA levels fell during therapy (median, 401 pg/40 microliters serum; range, 4-3, 100) vs. pretreatment levels (median, 533 pg/40 microliters; range, 30-4, 175), but in none was HBV-DNA undetectable at any stage. Within 1 month, the HBV-DNA had risen to pretreatment levels in all but one patient (with the lowest pretreatment level), who cleared HBeAg and developed anti-HBe within 3 months. Two further patients were anti-HBe positive at 6 months, but their pretreatment serum HBV-DNA levels were already low, suggesting a high probability of spontaneous seroconversion. Toxicity was not evident with the continuous infusion, but for those receiving IV bolus therapy, serum creatinine and phosphate levels rose in three of four patients, necessitating a 25% dose reduction. There was no difference in the effect on serum HBV-DNA between the two regimes. We conclude that foscarnet has only modest antiviral activity in chronic HBV carriers.

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The relation between viral replication, the presence of HBsAg and pre-S2 in serum and eventual clinical outcome has been investigated in fourteen patients undergoing treatment with lymphoblastoid interferon for chronic hepatitis B virus (HBV) infection. In four patients permanent loss of pre-S2 was accompanied by loss of serum HBV-DNA in association with a marked elevation of serum aspartate aminotransferase activity and in each of these cases HBsAg was subsequently cleared from serum. In contrast there was no significant fluctuation in the concentration of either pre-S2 or HBsAg in four cases not responding to therapy although substantial or complete inhibition of viral replication had been observed during treatment. In the third group, permanent loss of HBV-DNA was observed but in these cases pre-S2 and HBsAg persisted in serum, albeit at lower concentrations, while in this group loss of HBV-DNA from serum was not accompanied by a flare in disease activity. These results suggest first, that assay of pre-S2 is a further measure of the response to interferon and second that in some cases interferon enhances immune recognition of both the pre-S2 and HBsAg polypeptides.

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46 male chronic hepatitis B virus (HBV) carriers with active viral replication were randomised, with stratification for histology and sexual preference, to receive six months' lymphoblastoid interferon or no therapy. After nine to eighteen months' follow-up, HBeAg was no longer detectable and anti-HBe was present in 6 of the 23 treated patients. HBsAg was not detectable in 5 of these patients and 3 had anti-HBs. All of the controls remained positive for HBeAg and HBsAg. Seroconversion from HBeAg to anti-HBe was preceded in all cases by a pronounced increase in serum aspartate aminotransferase levels of more than ten times the upper limit of normal at eight to twelve weeks; this response was exclusively associated with interferon therapy. These results suggest that loss of HBsAg and a hepatitis-like illness in the third month of therapy are direct effects of interferon treatment.

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